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Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endoth...
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Zeitschriftentitel: | Molecular Cancer Therapeutics |
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Personen und Körperschaften: | , , , , , , |
In: | Molecular Cancer Therapeutics, 5, 2006, 1, S. 129-137 |
Format: | E-Article |
Sprache: | Englisch |
veröffentlicht: |
American Association for Cancer Research (AACR)
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author_facet |
Kondo, Seiji Tanaka, Noriko Kubota, Satoshi Mukudai, Yoshiki Yosimichi, Gen Sugahara, Toshio Takigawa, Masaharu Kondo, Seiji Tanaka, Noriko Kubota, Satoshi Mukudai, Yoshiki Yosimichi, Gen Sugahara, Toshio Takigawa, Masaharu |
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author |
Kondo, Seiji Tanaka, Noriko Kubota, Satoshi Mukudai, Yoshiki Yosimichi, Gen Sugahara, Toshio Takigawa, Masaharu |
spellingShingle |
Kondo, Seiji Tanaka, Noriko Kubota, Satoshi Mukudai, Yoshiki Yosimichi, Gen Sugahara, Toshio Takigawa, Masaharu Molecular Cancer Therapeutics Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells Cancer Research Oncology |
author_sort |
kondo, seiji |
spelling |
Kondo, Seiji Tanaka, Noriko Kubota, Satoshi Mukudai, Yoshiki Yosimichi, Gen Sugahara, Toshio Takigawa, Masaharu 1535-7163 1538-8514 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1535-7163.mct-05-0097 <jats:title>Abstract</jats:title> <jats:p>Connective tissue growth factor (CTGF/CCN2) is a potent angiogenic factor. In this report, we describe for the first time that vascular endothelial growth factor (VEGF)–mediated induction of the ctgf/ccn2 gene was a post-transcriptional event that was inhibited by a novel angiogenic inhibitor, DN-9693, in human umbilical vein endothelial cells. Steady-state mRNA levels of ctgf/ccn2 were remarkably increased by VEGF in a concentration-dependent manner, whereas the activity of the ctgf/ccn2 promoter was not responsive to VEGF as confirmed by a reporter gene assay and quantitative real-time PCR analysis. By employing a RNA degradation assay, we eventually found that the observed increase in the ctgf/ccn2 mRNA level was due to an increased stability of the mRNA induced by VEGF. DN-9693 at a dose of 0.1 to 2 ng/mL did not affect basal levels of ctgf/ccn2 mRNA; however, enhancement of ctgf/ccn2 mRNA expression by VEGF was specifically inhibited by DN-9693. Of importance, the inhibitory effects could be also ascribed to post-transcriptional regulation, because the VEGF-mediated increase in stability of ctgf/ccn2 mRNA was suppressed by DN-9693. Furthermore, we investigated the effects of DN-9693 on VEGF-induced activation of three subgroups of mitogen-activated protein kinase pathways and found that DN-9693 blocked the activation of these pathways by VEGF. These results suggest that VEGF increases ctgf/ccn2 mRNA stability through mitogen-activated protein kinase–mediated intracellular signaling cascade(s), which can be inhibited posttranscriptionally by a novel angiogenic inhibitor, DN-9693, in human umbilical vein endothelial cells. [Mol Cancer Ther 2006;5(1):129–37]</jats:p> Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells Molecular Cancer Therapeutics |
doi_str_mv |
10.1158/1535-7163.mct-05-0097 |
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Medizin |
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American Association for Cancer Research (AACR), 2006 |
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American Association for Cancer Research (AACR), 2006 |
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1535-7163 1538-8514 |
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American Association for Cancer Research (AACR) |
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title |
Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells |
title_unstemmed |
Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells |
title_full |
Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells |
title_fullStr |
Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells |
title_full_unstemmed |
Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells |
title_short |
Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells |
title_sort |
novel angiogenic inhibitor dn-9693 that inhibits post-transcriptional induction of connective tissue growth factor (ctgf/ccn2) by vascular endothelial growth factor in human endothelial cells |
topic |
Cancer Research Oncology |
url |
http://dx.doi.org/10.1158/1535-7163.mct-05-0097 |
publishDate |
2006 |
physical |
129-137 |
description |
<jats:title>Abstract</jats:title>
<jats:p>Connective tissue growth factor (CTGF/CCN2) is a potent angiogenic factor. In this report, we describe for the first time that vascular endothelial growth factor (VEGF)–mediated induction of the ctgf/ccn2 gene was a post-transcriptional event that was inhibited by a novel angiogenic inhibitor, DN-9693, in human umbilical vein endothelial cells. Steady-state mRNA levels of ctgf/ccn2 were remarkably increased by VEGF in a concentration-dependent manner, whereas the activity of the ctgf/ccn2 promoter was not responsive to VEGF as confirmed by a reporter gene assay and quantitative real-time PCR analysis. By employing a RNA degradation assay, we eventually found that the observed increase in the ctgf/ccn2 mRNA level was due to an increased stability of the mRNA induced by VEGF. DN-9693 at a dose of 0.1 to 2 ng/mL did not affect basal levels of ctgf/ccn2 mRNA; however, enhancement of ctgf/ccn2 mRNA expression by VEGF was specifically inhibited by DN-9693. Of importance, the inhibitory effects could be also ascribed to post-transcriptional regulation, because the VEGF-mediated increase in stability of ctgf/ccn2 mRNA was suppressed by DN-9693. Furthermore, we investigated the effects of DN-9693 on VEGF-induced activation of three subgroups of mitogen-activated protein kinase pathways and found that DN-9693 blocked the activation of these pathways by VEGF. These results suggest that VEGF increases ctgf/ccn2 mRNA stability through mitogen-activated protein kinase–mediated intracellular signaling cascade(s), which can be inhibited posttranscriptionally by a novel angiogenic inhibitor, DN-9693, in human umbilical vein endothelial cells. [Mol Cancer Ther 2006;5(1):129–37]</jats:p> |
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author | Kondo, Seiji, Tanaka, Noriko, Kubota, Satoshi, Mukudai, Yoshiki, Yosimichi, Gen, Sugahara, Toshio, Takigawa, Masaharu |
author_facet | Kondo, Seiji, Tanaka, Noriko, Kubota, Satoshi, Mukudai, Yoshiki, Yosimichi, Gen, Sugahara, Toshio, Takigawa, Masaharu, Kondo, Seiji, Tanaka, Noriko, Kubota, Satoshi, Mukudai, Yoshiki, Yosimichi, Gen, Sugahara, Toshio, Takigawa, Masaharu |
author_sort | kondo, seiji |
container_issue | 1 |
container_start_page | 129 |
container_title | Molecular Cancer Therapeutics |
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description | <jats:title>Abstract</jats:title> <jats:p>Connective tissue growth factor (CTGF/CCN2) is a potent angiogenic factor. In this report, we describe for the first time that vascular endothelial growth factor (VEGF)–mediated induction of the ctgf/ccn2 gene was a post-transcriptional event that was inhibited by a novel angiogenic inhibitor, DN-9693, in human umbilical vein endothelial cells. Steady-state mRNA levels of ctgf/ccn2 were remarkably increased by VEGF in a concentration-dependent manner, whereas the activity of the ctgf/ccn2 promoter was not responsive to VEGF as confirmed by a reporter gene assay and quantitative real-time PCR analysis. By employing a RNA degradation assay, we eventually found that the observed increase in the ctgf/ccn2 mRNA level was due to an increased stability of the mRNA induced by VEGF. DN-9693 at a dose of 0.1 to 2 ng/mL did not affect basal levels of ctgf/ccn2 mRNA; however, enhancement of ctgf/ccn2 mRNA expression by VEGF was specifically inhibited by DN-9693. Of importance, the inhibitory effects could be also ascribed to post-transcriptional regulation, because the VEGF-mediated increase in stability of ctgf/ccn2 mRNA was suppressed by DN-9693. Furthermore, we investigated the effects of DN-9693 on VEGF-induced activation of three subgroups of mitogen-activated protein kinase pathways and found that DN-9693 blocked the activation of these pathways by VEGF. These results suggest that VEGF increases ctgf/ccn2 mRNA stability through mitogen-activated protein kinase–mediated intracellular signaling cascade(s), which can be inhibited posttranscriptionally by a novel angiogenic inhibitor, DN-9693, in human umbilical vein endothelial cells. [Mol Cancer Ther 2006;5(1):129–37]</jats:p> |
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spelling | Kondo, Seiji Tanaka, Noriko Kubota, Satoshi Mukudai, Yoshiki Yosimichi, Gen Sugahara, Toshio Takigawa, Masaharu 1535-7163 1538-8514 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1535-7163.mct-05-0097 <jats:title>Abstract</jats:title> <jats:p>Connective tissue growth factor (CTGF/CCN2) is a potent angiogenic factor. In this report, we describe for the first time that vascular endothelial growth factor (VEGF)–mediated induction of the ctgf/ccn2 gene was a post-transcriptional event that was inhibited by a novel angiogenic inhibitor, DN-9693, in human umbilical vein endothelial cells. Steady-state mRNA levels of ctgf/ccn2 were remarkably increased by VEGF in a concentration-dependent manner, whereas the activity of the ctgf/ccn2 promoter was not responsive to VEGF as confirmed by a reporter gene assay and quantitative real-time PCR analysis. By employing a RNA degradation assay, we eventually found that the observed increase in the ctgf/ccn2 mRNA level was due to an increased stability of the mRNA induced by VEGF. DN-9693 at a dose of 0.1 to 2 ng/mL did not affect basal levels of ctgf/ccn2 mRNA; however, enhancement of ctgf/ccn2 mRNA expression by VEGF was specifically inhibited by DN-9693. Of importance, the inhibitory effects could be also ascribed to post-transcriptional regulation, because the VEGF-mediated increase in stability of ctgf/ccn2 mRNA was suppressed by DN-9693. Furthermore, we investigated the effects of DN-9693 on VEGF-induced activation of three subgroups of mitogen-activated protein kinase pathways and found that DN-9693 blocked the activation of these pathways by VEGF. These results suggest that VEGF increases ctgf/ccn2 mRNA stability through mitogen-activated protein kinase–mediated intracellular signaling cascade(s), which can be inhibited posttranscriptionally by a novel angiogenic inhibitor, DN-9693, in human umbilical vein endothelial cells. [Mol Cancer Ther 2006;5(1):129–37]</jats:p> Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells Molecular Cancer Therapeutics |
spellingShingle | Kondo, Seiji, Tanaka, Noriko, Kubota, Satoshi, Mukudai, Yoshiki, Yosimichi, Gen, Sugahara, Toshio, Takigawa, Masaharu, Molecular Cancer Therapeutics, Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells, Cancer Research, Oncology |
title | Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells |
title_full | Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells |
title_fullStr | Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells |
title_full_unstemmed | Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells |
title_short | Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells |
title_sort | novel angiogenic inhibitor dn-9693 that inhibits post-transcriptional induction of connective tissue growth factor (ctgf/ccn2) by vascular endothelial growth factor in human endothelial cells |
title_unstemmed | Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells |
topic | Cancer Research, Oncology |
url | http://dx.doi.org/10.1158/1535-7163.mct-05-0097 |